IFN-γ is an effector cytokine of cell-mediated immunity that plays an essential role in both innate and adaptive phases of an immune response. Interestingly, in several Th1-dependent autoimmune models, lack of IFN-γ is associated with an acceleration of disease. To distinguish the influence of IFN-γ on the polarization of naive precursors from the influence on effector cells, we used an adoptive transfer model of differentiated Ag-specific Th1 cells. In this study, IFN-γ displayed a dual function in a Th1-dependent immune reaction. In the early phase, IFN-γ accelerated the inflammation, whereas in the late phase it mediated the process of self-limitation. We demonstrated that IFN-γ limits the number of Th1 effector cells after Ag challenge. Studies using IFN-γR−/− mice as recipients showed that IFN-γ acts indirectly via host cells to regulate the pool size of Th1 cells. NO was a downstream effector molecule. Transfer experiments of Th1 cells into IFN-γ−/− mice revealed that Th1 cells control both themselves and the corresponding inflammation by the release of IFN-γ. Thus, the proinflammatory cytokine IFN-γ can act as a negative feedback regulator to control Th1-mediated immune responses.